The objectives of this project are to test the general validity of the two most prominent mechanisms of halothane induced liver damage (metabolic and immunologic) and also to test for synergism between the two mechanisms. Part I will develop, if possible, in mice and guinea pigs the enzyme induced, hypoxic model of "halothane hepatitis" which has already been developed in rats. First, the three species will be induced with phenobarbital to metabolize halothane at the same rate. Then, the exposure time to halothane and hypoxia required to produce the same extent of liver damage in the three species will be determined. Part II will determine the ability of rats, mice and guinea pigs to respond immunologically to metabolites of halothane presented a) as human serum albumin haptens, and b) as microsomal preparations from animals anesthetized with halothane under hypoxic conditions. Haptens will be injected into the foot pads, the humoral response will be determined using the Farr assay for antibody, and the cellular response will be determined using skin tests and a macrophage migration inhibition assay. Part III will determine if hypersensitivity will exacerbate the liver damage caused by hypoxia and halothane. Phenobarbital induced animals, both hypersensitive and controls, will be exposed to halothane and hypoxia to determine if a synergism exists.